The objective of the proposed research is to elucidate the mechanisms by which certain polyribonucleotides inhibit the growth of cancer cells. There have been numerous reports of the antitumor activity of exogenous polynucleotides. In cases of virus-induced tumors these effects may be in part due to the induction of interferon by double-stranded polynucleotides. However, antitumor effects have also been reported in cases where viral etiology is obscure. Both single and double stranded ribopolynucleotides can exert direct cytotoxic effects on some mammalian cells in vitro, but it is not yet clear if specific polynucleotides exist which are selectively cytotoxic for cancer cells. It has been reported that double stranded polynucleotides, as well as bacterial endotoxins can potentiate the ability of peritoneal macrophages to destroy normal and tumor cells in vitro. Thus polyribonucleotides have both direct and indirect anti-tumor effects. We propose to investigate three areas which may help to determine the mechanism of the antitumor effects of single and double stranded polynucleotides. First, we wish to study the binding and uptake of exogenous single and double stranded polynucleotides, by several cell types derived from normal and cancerous tissues, in order to delineate the biophysical basis of cell-polynucleotide interactions and the relationship between cell binding to biological effects. We have already made some detailed investigations in this area. One observation we intend to pursue are the possible effects of double stranded polynucleotide formation from complementary single strands at the cell surface on cell metabolism and on cell interactions. Second, we wish to assess direct and selective cytotoxicity of polynucleotides towards tumor cells both in vitro and in vivo. We have made initial observations in this area. Third, we wish to study the molecular mechanism whereby double stranded polynucleotides stimulate aggressive behavior by macrophages. We also wish to ascertain if this type of stimulation is manifested on other cells such as lymphocytes.